A major goal of neuroscience is to understand the mechanisms mediating brain plasticity. Among humans, seasonal alterations in mood, immune function, and response to brain damage are well-documented. We recently established an experimental model of photoperiod-induced plasticity in brain structure and function. Male Peromyscus mice reduce hippocampal size and spatial memory performance in short days; short days decrease apical CA1 spine density and increase basilar CA3 spine density suggesting that photoperiod, encoded by melatonin, alters brain structure and cognitive function. We will use this system to understand the factors driving such changes. Aim 1: What aspects of brain morphology and cognitive function respond to photoperiod or melatonin? We will study changes in: (1) hippocampal volume/dendritic morphology, (2) hippocampal neurogenesis, (3) long-term potentiation (LTP), and (4) learning and memory. Aim 2: What is the role of gonadal steroid hormones in mediating photoperiod-induced brain plasticity? We will examine aromatase activity, androgen (AR), and estrogen receptor (ER) subtype (ER1 and ER2) expression in long- vs. short-day mice, and determine whether gonadectomy or treatment with AR and/or ER receptor antagonists eliminates photoperiodic differences in brain plasticity. Aim 3: How does photoperiod and androgen affect brain-derived neurotrophic factor (BDNF), and brain plasticity? Using qRT-PCR, photoperiod and androgen effects on BDNF will be assessed. Aim 4: What is the time course by which photoperiod affects brain and behavioral plasticity? We will examine mice at different time points during the switch between photoperiods. Also, because season of birth influences many human neurological disorders, we will examine the enduring effects of photoperiod on brain and behavior of mice born in long or short days, then reared in the same or opposite photoperiod. Our combinatorial approach will provide insight into the treatment of seasonal cognitive and affective disorders, developmental disabilities, and help establish general mechanisms underlying brain plasticity. PUBLIC HEALTH RELEVANCE The role of photoperiod on brain and behavioral plasticity is understudied. Traditionally, neuroscientists interested in seasonal brain plasticity have focused on songbirds. This proposal adds a novel dimension to the study of seasonality, as well as the study of brain and behavioral plasticity. The working hypothesis underlying all of our proposed studies is that short days are associated with individuals switching resources to gain energetic savings. In other words, we visualize short-day changes in brain and hippocampal size, dendritic spines, neurogenesis, and spatial learning and memory performance as adaptations due to changing energetic conditions that are dependent on photoperiod, biological clocks, and melatonin. Of particular importance is the postulate that seasonal variation in certain human disorders may be due at least in part to variation in photoperiodic effects of brain structure and function. The evolutionary history of humans suggests that almost all ancestral stocks of Homo sapiens have lived at one time or another in situations where seasonal adjustments in physiology might have proven advantageous. Although the available data suggest that modern human reproduction is not susceptible to photoperiodic regulation, brain plasticity and behavioral function very well might be. This possibility deserves serious consideration. Importantly, seasonal changes in neuroendocrine function, hypothalamic expression of vasopressin, vasoactive intestinal polypeptide (VIP), and serotonin function have also been reported in humans. Seasonal changes in human behavioral pathology are also observed in anxiety and depression, migraine headaches, as well as incidence, severity, and mortality of strokes. Thus, despite the relative lack of seasonal organization of reproductive function, it is apparent that humans retain responsiveness to photoperiod, and that photoperiod-mediated adjustments in rodent brain and behavior may be important to understand seasonal changes in human brain and behavior.